1. Field of the Invention
The present invention relates to novel tripeptide derivatives and more particularly, to tripeptide derivatives or pharmaceutically acceptable salts thereof which can inhibit a proteases and to protease inhibitor compositions comprising the tripeptide derivatives or salts thereof as an effective ingredient.
2. Statement of the Prior Art
It is well known that a variety of proteases are present in vivo. For example, there are known trypsin-like enzymes such as plasmin, trypsin, kallikrein, thrombin, urokinase, etc.; chymotrypsin-like enzymes; pepsin-like enzymes, etc. These proteases are known to cause various diseases when these enzymes are abnormally activated by some reasons. For example, when a large amount of plasmin formed by abnormal activation is present in blood, a hemorrhagic disease is caused. Plasmin takes part also in inflammation, increases blood permeability of a blood vessel, causes edemata, etc. and develops inflammatory diseases. Accordingly, substances having an inhibitory activity against these proteases are useful as drugs for some clinical treatments and various investigations on these substances have been made heretofore. For example, an anti-plasmin agent is useful as a hemostatic, antiinflammatory and anti-allergic agent; an anti-thrombin agent is useful for the treatment of thrombosis; an anti-trypsin agent is useful for the treatment of pancreatitis; an anti-kallikrein agent is useful for the treatment of inflammation and ulcer; and an anti-urokinase agent is useful for the prevention of hemorrhagic conditions in thrombolytic therapy by urokinase. Protease inhibitors having such activities were thus extensively investigated heretofore. However, the inhibitory activity of these proteases is poor and still insufficient to provide them as drugs for practical use. Any compounds having a sufficient inhibitory activity against several proteases have not been developed so far.
For example, some tripeptide derivatives containing argininal groups are widely known as a protease inhibitor. Acetyl-L-leucyl-L-leucyl-L-argininal (leupeptin) is a compound produced by a certain microorganism (see, e.g., J. Antibiotics (Tokyo), 1969, vol. 22, page 283) but its inhibitory activity is poor (see, e.g., Taisha, 1977, vol. 14, No. 6, page 1087). D-Phenylalanyl-L-prolyl-L-argininal is known as a thrombin inhibitor (e.g., Symposia Biologica Hungarica, 1984, vol. 25, page 277) but its inhibitory activities against other similar trypsin-like enzymes are poor. Furthermore, Umezawa et al. synthesized a number of leupeptin derivatives but any of them has a poor inhibitory activity against a trypsin-like enzyme (see J. Antibiotics (Tokyo), 1988, vol. 41, No. 2, page 220).